Use of (+)-α-(2,3-dimethoxyphenyl-1-[2-(4-fluorophenyl)ethyl]-4-piperidin emethanol in treating depressive disorders and bipolar disorders

ABSTRACT

The present invention is directed to the use of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol in treating Depressive Disorders and Bipolar Disorders.

This is a continuation of patent Ser. No. 08/823,658 filed Mar. 17,1997, now abandoned.

The present invention is directed to the use of compound(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolor its pharmaceutically acceptable acid addition salts in a method oftreating Depressive Disorders and Bipolar Disorders in patients in needof such therapy.

BACKGROUND OF THE INVENTION

The compound (+)-isomer ofα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolis generically described by U.S. Pat. No. 5,169,096 and specificallydescribed in U.S. Pat. No. 5,134,149, both of which are herebyincorporated by reference. This compound is described therein as a5HT_(2A) receptor antagonist. It has since been discovered that thiscompound is useful in the treatment of Depressive Disorders and BipolarDisorders.

The compound of the present invention solves the complicated problem oftreating patients for Depression Disorders or Bipolar Disorders throughan unusual compound profile. It is a highly selective 5HT_(2A) receptorantagonist having subnanomolar affinity for the 5HT_(2A) receptor versusaffinities of greater than 100 nM for the 5HT_(2c), D₁ (dopamine), D₂(dopamine), and α-1 receptors in in vitro models.

It has a lower affinity for receptors often associated with unwantedside effects, e.g., lower affinity for the D₂ receptor suggests lesspotential to cause extrapyramidal side effects, little affinity for thecholinergic M1/M2 receptors suggests less cholinergic side effects suchas dry mouth, delirium and cognitive impairment. It is orally active,non-toxic at therapeutic doses and potent. It is also capable of beingscaled-up for commercial synthesis. Additionally, neurochemical studiesindicate that there is a serotonin/dopamine interaction followingchronic administration of this compound as described in Life Sciences56(25): 2209-2222 (1995), incorporated herein by reference. Thecombination of the foregoing characteristics produces a unique compoundfor treating patients having either Depressive Disorders or BipolarDisorders.

SUMMARY OF THE INVENTION

In accordance with the present invention, a compound has been discoveredwhich is useful in the treatment of Depressive Disorders and BipolarDisorders, the (+)-isomer ofα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolor the pharmaceutically acceptable salts thereof. It is described by thefollowing formula: ##STR1##

A therapeutically effective amount of this compound or itspharmaceutically acceptable acid addition salt is administered to apatient in need of such therapy to treat Depressive Disorders or BipolarDisorders.

DETAILED DESCRIPTION OF THE INVENTION

As used in this application:

a) the expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of the compound of the present invention. Illustrative inorganicacids which form suitable salts include hydrochloric, hydrobromic,sulfuric and phosphoric acid and acid metal salts such as sodiummonohydrogen orthophosphate and potassium hydrogen sulfate. Illustrativeorganic acids which form suitable salts include the mono-, di- andtri-carboxylic acids. Illustrative of such acids are, for example,acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric,malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic,hydroxybenzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxybenzoic,p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acidand 2-hydroxyethanesulfonic acid. Either the mono- or di-acid sales canbe formed, and such salts can exist in either a hydrated orsubstantially anhydrous form. In general, the acid addition salts ofthese compounds are soluble in water and various hydrophilic organicsolvents and which in comparison to their free base forms, generallydemonstrate higher melting points.

b) any reference to(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolshould be construed as encompassing the free base of this compound or anacid addition salt of this compound.

c) the term "patient" refers to a warm-blooded animal, such as forexample rats, mice, dogs, cats, guinea pigs, and primates such ashumans, and;

d) the term "treat" refers to either relieving or alleviating thepatient's disease or condition.

The (+)-isomer ofα-(2,3-dimethoxyphenyl)-1-(2-(4-fluorophenyl)ethyl]-4-piperidinemethanolcan be prepared by methods known in the art as was discussed in EuropeanApplication 0 208 235 (U.S. Pat. No. 5,169,096). One suitable method isdisclosed below in Reaction Scheme I: ##STR2##

In Step A of Reaction Scheme I, an esterification reaction is carriedout between racemicα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol(structure 1) and the (+)-isomer of α-methoxyphenylacetic acid(structure 2). This esterification produces the diastereomeric mixtureidentified as structure 3. These diastereomers are subjected to silicagel chromatography which separates the two diastereomers, therebyisolating the (+,+) diastereomer as is depicted in Step B. In Step C,the (+,+) diastereomer is hydrolysed which produces the (+)-isomer ofα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.

The esterification reaction can be carried out using techniques known inthe art. Typically approximately equivalent amounts of racemicα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanoland the (+)-isomer of α-methoxyphenylacetic acid are contacted in anorganic solvent such as methylene chloride, THF, chloroform, toluene andheated to reflux for a period of time ranging from 5 to 24 hours. Theesterification is typically carried out in the presence of an equivalentamount of dicyclohexylcarbodiimide and a catalytic amount of4-dimethylaminopyridine. The resulting diastereomers can be isolated byfiltration of the dicyclohexylurea and evaporation of the filtrate.

The diastereomers are then subjected to silica gel chromatograpy whichseparates the (+,+) and the (-,+) diastereomers. This chromatagraphicseparation may be carried out as is known in the art. A 1:1 mixture ofhexane and ethyl acetate is one suitable eluent.

The resulting (+,+) diastereomer is then subjected to a hydrolysisreaction which produces the (+)-isomer ofα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.The hydrolysis is carried out by contacting the diastereomer with anexcess of a base such as potassium carbonate in an aqueous alcoholicsolution. The hydrolysis is carried out at a temperature of about 15 to30° C. for a period of time ranging from 2 to 24 hours. The resulting(+)-isomer ofα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolmay then be recovered by dilution with water and extraction withmethylene chloride. It is then purified by recrystallization from asolvent system such as cyclohexane/hexane or ethyl acetate/hexane.

Methods for producing the starting materials of Reaction Scheme I areknown in the art. For example, U.S. Pat. No. 4,783,471 teaches how toprepare racemicα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.This patent is hereby incorporated by reference. Examples No. 1 and 2 ofthis application also teach suitable methods. Alternatively, racemicα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolcan be prepared in the following manner. Initially In-hydroxypiperidineis subjected to an N-alkylation reaction with p-fluorophenylethylbromide which produces 4-hydroxy-1-[2-(4-fluorophenyl)ethyl]-piperidine.This compound is brominated with Ph₃ P.Br₂ which produces4-bromo-1-[2-(4-fluorophenyl)ethyl]piperidine. This compound iscontacted with Mg thereby forming a Grignard Reagent which is thenreacted with 2,3-dimethoxybenzaldehyde which produces the desiredproduct(±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.The (+)-isomer of α-methoxyphenylacetic acid is known in the art.

The dosage range at which(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolexhibits its ability to treat Depressive Disorders (anti-depressivedisorder amount) or Bipolar Disorders (anti-bipolar disorder amount) canvary depending upon the particular disease or condition being treatedand its severity, the patient, other underlying disease states thepatient is suffering from, and other medications that may beconcurrently administered to the patient. Generally though, thiscompound will exhibit its anti-Depressive Disorder or anti-BipolarDisorder properties at a dosage range of from about 0.001 mg/kg ofpatient body weight/day to about 100.0 mg/kg of patient body weight/day.Preferably five (5) to twenty (20) mg. per dose is administered twicedaily. The compound is typically administered from 1-4 times daily.Alternatively, it can be administered by continuous infusion. Thecompounds can be administered orally or parenterally to achieve theseeffects.

The compound of the present invention can be formulated intopharmaceutical dosage forms using techniques well known in the art. Fororal administration, the compound can be formulated into solid or liquidpreparations such as capsules, pills, tablets, lozenges, melts, powders,suspensions, or emulsions. Solid unit dosage forms can be capsules ofthe ordinary gelatin type containing, for example, surfactants,lubricants and inert fillers such as lactose, sucrose, and cornstarch orthey can be sustained release preparations. In another embodiment, thecompound can be tableted with conventional tablet bases such as lactose,sucrose, and cornstarch in combination with binders, such as acacia,cornstarch, or gelatin, disintegrating agents such as potato starch oralgenic acid, and a lubricant such as stearic acid or magnesiumstearate. Liquid preparations are prepared by dissolving the activeingredient in an aqueous or non-aqueous pharmaceutically acceptablesolvent which may also contain suspending agents, sweetening agents,flavoring agents, and preservative agents as are known in the art.

For parenteral administration, the compound or its salts may bedissolved in a physiologically acceptable pharmaceutical carrier andadministered as either a solution or a suspension. illustrative ofsuitable pharmaceutical carriers are water, saline, dextrose solutions,fructose solutions, ethanol, or oils of animal, vegetative, or syntheticorigin. The pharmaceutical carrier may also contain preservatives,buffers, etc. as are known in the art.

The compounds of this invention can also be administered topically. Thiscan be accomplished by simply preparing a solution of the compound to beadministered, preferably using a solvent known to promote transdermalabsorption such as ethanol or dimethyl sulfoxide (DMSO) with or withoutother excipients. Preferably topical administration will be accomplishedusing a patch either of the reservoir and porous membrane type or of asolid matrix variety.

Some suitable transdermal devices are described in U.S. Pat. Nos.3,742,951, 3,797,494, 3,996,934, and 4,031,894. These devices generallycontain a backing member which defines one of its face surfaces, anactive agent permeable adhesive layer defining the other face surfaceand at least one reservoir containing the active agent interposedbetween the face surfaces. Alternatively, the active agent may becontained in a plurality of microcapsules distributed throughout thepermeable adhesive layer. In either case, the active agent is deliveredcontinuously from the reservoir or microcapsules through a membrane intothe active agent permeable adhesive, which is in contact with the skinor mucosa of the recipient. If the active agent is absorbed through theskin, a controlled and predetermined flow of the active agent isadministered to the recipient. In the case of microcapsules, theencapsulating agent may also function as the membrane.

In another device for transdermally administering the compound of thepresent invention, the pharmaceutically active compound is contained ina matrix from which it is delivered in the desired gradual, constant andcontrolled rate. The matrix is permeable to the release of the compoundthrough diffusion or microporous flow. The release is rate controlling.Such a system, which requires no membrane is described in U.S. Pat. No.3,921,636. At least two types of release are possible in these systems.Release by diffusion occurs when the matrix is non-porous. Thepharmaceutically effective compound dissolves in and diffuses throughthe matrix itself. Release by microporous flow occurs when thepharmaceutically effective compound is transported through a liquidphase in the pores of the matrix.

The compound may be admixed with any inert carrier and utilized inlaboratory assays in order to determine the concentration of thecompounds within the urine, serum, etc. of the patient as is known inthe art.

The following Examples are being presented to further illustrate theinvention. However, they should not be construed as limiting theinvention in any manner.

EXAMPLE 1

A) 1-[2-(4-Fluorophenyl)ethyl]-4-piperidinecarboxamide

A solution of isonipecotamide (10.9 g, 85.0 mmol),2-(4-fluorophenyl)ethyl bromide (15.7 g, 77.3 mmol), and K₂ CO₃ (2.3 g,167 mmol) was prepared in DMF (280 mL) and stirred under argon at 90-95°C. overnight. The cooled solution was concentrated to a white oilysolid. The solid was partitioned between water and CH₂ Cl₂. The layerswere separated and the aqueous layer was extracted with CH₂ Cl₂. Thecombined organic layers were washed 2× with water, dried (MgSO₄),filtered, and evaporated to a oily solid. The solid was recrystallizedfrom EtOAc to afford 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamideas a white powder, m.p. 177-178° C. (decomp.). Anal. Calcd for C₁₄ H₁₉FN₂ O: C, 67.18; H, 7.65; N, 11.19. Found: C, 67.25; H, 7.67; N, 11.13.

B) 4-Cyano-1-[2-(4-fluorophenyl)ethyl]piperidine

To stirred phosphorus oxychloride (25 mL, 41.12 g, 268 mmol) and sodiumchloride (5.1 g, 87.3 mmol) was added1-L[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide (8.9 g, 35.6 mmol)portionwise. After complete addition, the solution was refluxed for 2hours. The cooled solution was poured into dilute NH₄ OH to destroy thePOCl₃. The aqueous solution was cooled to 0° C., then extracted 2× withCH₂ Cl₂. The combined organic layers were dried (MgSO₄), filtered, andevaporated to afford 8.1 g of an oily solid. The solid as distilled,(b.p. 150° C., 0.1 mm Hg), to afford a clear, colorless oil thatsolidified. This material was crystallized from hexane to afford4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine as white needles, m.p.47-48° C. Anal. Calcd for C₁₄ H₁₇ FN₂ : C, 72.39; H, 7.38; N, 12.06.Found: C, 72.62; H, 7.49; N, 12.12.

C) 1-[2-(4-Fluorophenyl)ethyl]-4-piperidinecarboxaldehyde

To a stirred solution of 4-cyano-1-[2-(4-fluorophenyl)-ethyl]piperidine(1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0° C. was added DIBAL-H(4.6 mL of a 1.0 M solution in THF, 4.6 mmol) via syringe. Afterstirring overnight at room temperature, 10% aqueous HCl (25 mL) wasadded and the solution was stirred for 3 hours. The entire mixture wasthen poured into 10% aqueous NaOH (50 mL), then extractd 2× with ether.The combined organic layers were washed with brine, dried (MgSO₄),filtered, and evaporated to afford a pale yellow oil. The oil waschromatographed on silica gel, eluting with EtOAc. The appropriatefractions were combined and evaporated to afford an oil. This oil wasdistilled (b.p. 166° C., 0.05 mm Hg) to afford1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as acolorless oil. Anal. Calcd for C₁₄ H₁₈ FNO: C, 71.46; H, 7.71; N, 5.95.Found: C, 71.08, H, 7.81; N, 5.86.

D)(±)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol

To a stirred solution of veratrole (0.93 g, 6.7 mmol) in THF (20 mL)under argon at 0° C. was added n-BuLi (2.7 mL of a 2.5 M solution inhexane, 6.75 mmol). After stirring 2.5 h, the solution was cooled to-78° C. and treated with1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde (1.30 g, 5.5mmol) in THF (25 mL) via an addition funnel. The cooling bath wasremoved and the solution was allowed to stir for 2 hours. Water wasadded, the layers separated, and the aqueous layer was extracted withEtOAc. The combined organic layers were washed with brine, dried(MgSO₄), filtered, and chromatographed on silica gel, eluting withacetone. The appropriate fractions were combined and evaporated toafford a white solid. The solid was recrystallized from hexane to affordracemicα-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolas shiny white needles, m.p. 126-127° C. Anal. Calcd for C₂₂ H₂₈ FNO₃ :C, 70.75; H, 7.56; N, 3.75. Found: C, 70.87; H, 7.65; N, 3.68.

EXAMPLE 2

Example 2, Steps A-F, demonstrate an alternative manner of preparing(±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol,structure 1.

A) 1-(1,1-Dimethylethyl)-1,4-piperidinedicarboxylic acid

To isonipecotic acid (107.5 g, 832 mmol) stirred in 1N NaOH (40 g NaOHin 900 mL H₂ O) and tert-butanol (1800 mL) was added di-tert-butyldicarbonate (200 g, 916 mmol) in portions. After stirring overnight, thesolution was concentrated and the resulting water layer was acidifiedwith aqueous HCl. This acidic aqueous layer was extracted 3× with ether.The combined organic layers were washed with water, brine, dried(MgSO₄), filtered, and evaporated to a white solid, which wasrecrystallized from EtOAc/hexane (300 mL/200 mL) to afford 1-(1,1-dimethyl-ethyl)-1,4-piperidinedicarboxylic acid as white needles, m.p.147-149° C.

B) 4-(N-Methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid1,1-dimethylethyl ester

To a stirred solution of1-(1,1-dimethylethyl)-1,4-piperidinedicarboxylic acid (50.0 g, 218 mmol)in anhydrous H₂ Cl₂ (500 mL) under N₂ in a 2L flask was added1,1'-carbonyldiimidazole (38.9 g, 240 mmol) portionwise. After stirringfor 1 hour, N,O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol)was added in one portion. After stirring overnight, the solution waswashed twice with 1N HCl, twice with saturated NaHCO3, once with brine,dried (MgSO₄), filtered, and evaporated to an oil. Distillation afforded4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid1,1-dimethylethyl ester as a clear oil, b.p. 120-140° C., 0.8 mm.

C)4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethylester

n-Butyl lithium (14.5 mL of a 2.5 M solution in hexane, 36.3 mmol) wasadded via syringe to a stirred solution of veratrole (5.00 g, 36.2 mmol)in THF (50 mL, anhydrous) under argon at 0° C. The ice bath was removedand the mixture was allowed to stir for 90 minutes. The mixture wascooled to -78° C. and treated with4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid1,1-dimethylethyl ester (9.20 g, 33.8 mmol) in THF (50 mL, anhydrous)via syringe. The cooling dry ice-acetone bath was removed and themixture was allowed to come to room temperature. After stirring for 3hours, saturated aqueous NH₄ Cl was added and the mixture was allowed tostir overnight. The layers were separated and the aqueous layer wasextracted with ether. The combined organic layers were washed withbrine, dried (MgSO₄), filtered, and evaporated to afford an amber oil.The oil was chromatographed on silica gel, eluting with 20% EtOAc inhexane. The appropriate fractions were combined and evaporated to anamber oil. The oil was distilled to afford4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethylester as a colorless oil.(b.p. 225-250° C., 0.05 mm). Anal. Calcd forC₁₉ H₂₇ NO₅ : C, 65.31; H, 7.79; N, 4.01. Found: C, 65.04; H, 7.92; N,4.11.

D) 4-(2,3-Dimethoxyphenyl)-4-piperidinylmethanone

4-(2,3-Dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethylethylester (7.75 g, 22.2 mmol) was dissolved in trifluoroacetic acid (50 mL,650 mmol) and stirred for 45 minutes. The entire solution was pouredinto ether (900 mL) and allowed to stand overnight. Filtration yielded4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate as finewhite needles, m.p. 123° C. Anal. Calcd for C₁₄ H₁₉ NO₃ :CF₃ CO₂ H: C,52.89; H, 5.55; N, 3.86. Found: C, 52.77; H, 5.62; N, 3.82.

The resulting 4-(2,3-dimethoxyphenyl)-4-piperidinyl-methanonetrifluoroacetate was dissolved in water, treated with NaOH (10% aqueous)until basic, and extracted three times with dichloromethane. Thecombined organic layers were washed with brine, dried (MgSO₄), filtered,and evaporated to afford 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanoneas an oil.

E) (2,3-Dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methanone monohydrochloride

A solution of 4-(2,3-dimethoxyphenyl)-4-piperidinyl-methanone (8.00 g,32.1 mmol) and 2-(4-fluorophenyl)ethyl bromide (6.52 g, 32.1 mmol) wasprepared in DMF (90 mL), treated with K₂ CO₃ (7.0 g, 50.7 mmol), thenstirred and heated at 80° C. under argon overnight. The cooled solutionwas poured into a partition of 2/1 EtOAc/toluene and water. The layerswere separated and the aqueous layer was extracted with 2/1EtOAc/toluene. The combined organic layers were washed 2× with water, 1×with brine, dried (MgSO₄), filtered, and evaporated to afford 11.0 g ofan oil. The oil was chromatographed on silica gel, eluting with EtOAc.The appropriate fractions were combined, concentrated, dissolved inethyl acetate and treated with HCl/ethyl acetate.(2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]-methanonemonohydrochloride was obtained as a precipitate, m.p. 225-227° C.(decomp). Anal Calcd for C₂₂ H₂₆ FNO₃.HCl: C, 64.78; H, 6.67; N, 3.43.Found: C, 64.44; H, 6.73; N, 3.41.

F)(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

To a stirred solution of(2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methanone(6.0 g, 16.2 mmol) in MeOH (100 mL) at 0° C. was added NaBH₄ (1240 mg,32.8 mmol) in two portions, over a one hour period. After stirringovernight, the solution was concentrated to a solid. The solid waspartitioned between water and ether. The layers were separated and theaqueous layer was extracted with ether. The combined organic layers werewashed with brine, dried (MgSO₄), filtered, and evaporated to a solid.The solid was chromatographed on silica gel, eluting with acetone. Theappropriate fractions were combined and evaporated to afford a whitesolid. The solid was recrystallized from cyclohexane to afford(±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanolas white needles, m.p. 126-127° C. Anal.

Calcd for C₂₂ H₂₈ FNO₃ : C, 70.75; H, 7.56; N, 3.75. Found: C, 70.86; H,7.72; N, 3.93.

EXAMPLE 3

This example demonstrates the preparation of the compound of the presentinvention.

Preparation of(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol

A) Preparation of diastereomers.

A solution of 3.90 g (10.4 mmol) of(±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol,1.74 g (10.4 mmol) of S-(+)-α-methoxyphenylacetic acid, 2.15 g (10.4mmol) of 1,3-dicyclohexylcarbodiimide and 0.1 g of4-dimethylaminopyridine in chloroform (75 ml) was refluxed for 17 hours,allowed to cool to room temperature and filtered. The filtrate wasconcentrated and chromatographed on a silica gel column eluting withethyl acetate/hexane (1:1) to afford two diastereomers, Rf=0.1 and 0.2(TLC EtOAc/hexane, 1:1). Intermediate fractions were rechromatographedto give additional material. Those fractions with Rf=0.2 were combinedto give a single diastereomeric ester,(+,+)-(2,3-dimethoxyphenyl)[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methyl-α-methoxybenzeneacetate.

B) Preparation of(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluoroohenyl)ethyl]-4-pieridinemethanol

To a stirred solution of 0.97 g (1.9 mmol) of the above mentioneddiastereomeric ester, Rf=0.2, in 25 ml of methanol was added 0.5 g (3.6mmol) of potassium carbonate and 5.0 ml of water. After stirring 17hours at room temperature the reaction mixture was diluted with waterand extracted twice with methylene chloride. The combined extracts werewashed with water, brine and dried over MgSO₄. After filtering, thefiltrate was concentrated to an oil and crystallized from 40 ml ofcyclohexane/hexane (1:1) to give(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-30piperidinemethanol, m.p.112-113° C., [α]_(D) ²⁰ =+13.9°.

The compound of the present invention is useful in treating patientswith Depressive Disorders and Bipolar Disorders. In the Diagnostic andStatistical Manual of Mental Disorders (Third Edition-Revised)("DSM-III-R"), incorporated herein by reference, Depressive Disordersare defined as Major Depression, Dysthymia and Depressive Disorder NOS.We also include in this category Major Depressive Episode includingChronic Type, Melancholia, and Seasonal Pattern. Bipolar Disordersinclude Bipolar Disorder, Cyclothymia and Bipolar Disorder NOS.

A feature of Depressive Disorders is one or more periods of depressionwithout a history of either Manic or Hypomanic episodes. A feature ofBipolar Disorders is the presence of one or more Manic or HypomanicEpisodes usually accompanied by one or more Major Depressive Episodes. AManic or Hypomanic Episode is a distinct period during which thepredominant mood is either elevated, expansive or irritable and thereare associated symptoms of the Manic Syndrome as defined in DSM-III-R.The disturbance is severe enough to cause marked impairment inoccupational or social functioning.

Major Depression has one or more Major Depressive Episodes. A MajorDepressive Episode is characterized by: (1) at east five of thefollowing) depressed mood, loss of Interest in pleasure (anhedonia),significant weight loss or weight gain when not dieting, insomnia orhypersomnia, psychomotor agitation or retardation, fatigue or loss ofenergy, feelings of worthlessness or excessive or inappropriate guilt,diminished ability to think or concentrate, or recurrent thoughts ofdeath including suicide; (2) it cannot be established that an organicfactor initiated and maintained the disturbance; (3) there are nodelusions or hallucinations for as long as two weeks in the absence ofprominent mood symptoms; and (4) it is not superimposed onSchizophrenia, Schizophreniform Disorder, Delusional Disorder, orPsychotic Disorder NOS.

Dysthymia has a history of a depressed mood more days than not for atleast two years and during the first two years of the disturbance, thecondition does not meet the criteria for a Major Depressive Episode. Thedepressed mood in children and adolescents can be exhibited asirritability. Also present is at least two of the following: poorappetite or overeating, insomnia or hypersomnia, low energy or fatigue,low self-esteem, poor concentration or difficulty making decisions orfeeling of hopelessness. These symptoms are not superimposed on achronic psychotic disorder such as Schizophrenia or Delusional Disorder.Also it cannot be determined that an organic factor initiated andmaintained the disturbance.

There are many ways to show that the compound of the present inventionis useful in treating Depressive Disorders and Bipolar Disorders such asin animal models. See for example, "Animal Models as simulations ofdepression" by Paul Willner, TiPS 12:131-136 (April 1991); "AnimalModels of Depression: An overview" by Paul Willner, Pharmac. Ther.45:425-455 (1990), both of which are incorporated herein by reference.One such model is the Chronic Mild Stress Model of Depression ("CMS").

CMS uses mild stressors, such as food and water deprivation, smalltemperature changes, changes of cage mates, etc. Over a period of weeksof exposure to the mild stressors, the animals gradually reduce theirconsumption of a highly preferred sucrose solution which persists (inuntreated animals) for several weeks following the cessation of stress.This decreased sensitivity to reward (the sucrose solution) reflectsanhedonia, a symptom of a Major Depressive Episode (see for example,Behavioral Pharmacol.5: Suppl.l, p. 86 (1994) where lithium,carbamazepine and ketoconazole were evaluated in CMS; Psychopharmacology93:358-364 (1987) where a tricyclic antidepressant was evaluated in CMS;Behavioural Pharmacology:5:344-350 (1994) where a catechol-O-methyltransferase inhibitor was evaluated in CMS).

The following CMS study was performed using the compound of the presentinvention (hereafter "THE COMPOUND") in comparison to knownanti-depressant compound imipramine.

Male Wistar rats were brought into the laboratory two months before thestart of the experiment at which time they weighed aprroximately 300grams. Except as described below, the animals were singly housed, withfood an eater freely available, and maintained on a 12 hour light/darkcycle (lights on at 8AM) at a temperature of 22±° C.

The animals were first trained to consume a 1% sucrose solution;training consisted of eight 1 hour baseline tests in which sucrose waspresented, in the home cage, following 14 hours food and waterdeprivation; intake was measured by weighing pre-weighed bottlescontaining the sucrose solution at the end of the test. Subsequently,sucrose consumption was monitored, under similar conditions, at weeklyintervals throughout the whole experiment.

On the basis of their sucrose intakes in the final baseline test, theanimals were divided into two matched groups. One group of animals wassubjected to a chronic mild stress procedure for a period of 9consecutive weeks.

Each week of stress regime consisted of: two periods of food or waterdeprivation (12 and 14 hour), two periods of 45 degree cage tilt (12 and14 h), two periods of intermittent overnight illumination (lights on andoff every 2 hours), two 14 hour periods of soled cage (200 ml water insawdust bedding), two 14 hour periods of paired housing, two 14 hourperiods of low intensity stroboscopic illumination (150 flashes/min).Stressors were applied continuously throughout the day and night, andscheduled randomly. Control animals were housed in a separate room andhad no contract with the stressed animals. They were deprived of foodand water for the 14 hours preceding each sucrose test, but otherwisefood and water were freely available in the home cage. On the basis oftheir sucrose intake scores following 3 weeks of stress, both stressedand control animals were each divided further into matched subgroups(n=8), and for subsequent five weeks they received daily administrationsof vehicle (1m1/kg, intraperineally (ip)) imipramine (10 mg/kg, ip) orTHE COMPOUND (0.002, 0.02 and 0.2 mg/kg orally). All drug injectionswere in a volume of 1m1/kg body weight. Drugs were administered at 10 AMand sucrose tests were carried out 24 hours following the last drugtreatment. After five weeks, the treatments were terminated and afterone week of withdrawal a final sucrose test was carried out. Stress wascontinued throughout the period of treatment and withdrawal.

Results were analyzed by multiple analysis of variance, followed byFisher's LSD test for post hoc comparisons of means.

Chronic mild stress caused a gradual decrease in the consumption of 1%sucrose solution, in the final baseline test, sucrose intake wasapproximately 13 gram in both groups. Following three weeks of stress(Week 0), intakes remained at 12.4 (±0.4) grams in controls but fell to7.2 (±0.2) grams in stressed animals (p<0.001). Such a differencebetween control and stressed animals treated with vehicle, persisted atsimilar level for the remainder of the experiment.

Imipramine had no significant effect on the sucrose intake in controlanimals [F(1,84)=0.364; NS]. However, the drug caused a gradual increaseof sucrose intake in stressed animals (F(1,84)=16.776; p<0.001]. Sucroseintake in imipramine-treated stressed animals was significantlyincreased from Week 0 scores after four weeks of treatment (p=0.05) andafter five weeks of treatment there were no significant differencesbetween drug-treated stressed animals and drug- and saline-treatedcontrols. The increase of sucrose intake in imipramine-treated stressedanimals was maintained at similar level one week after withdrawal fromthe drug.

THE COMPOUND had no significant effect on the sucrose intake in controlanimals [Treatment effect:F(3,168)=0.821; NS Treatment x Weeksinteraction: F(15,168=0.499; NS]. In stressed animals, THE COMPOUNDgradually reversed the CMS-induced deficit in sucrose intake, resultingin a significant Treatment effect [F(3,168)=22.567; p<0.001] andTreatment x Weeks interaction (F(15,158)=1.559; p=0.05].

In stressed animals treated with two higher doses of THE COMPOUND (0.02and 0.2 mg/kg), sucrose intakes were significantly increased frominitial scores (Week 0) after two (0.02 mg/kg) and three (0.2 mg/kg)weeks of treatment (p=0.03 and p=0.04, respectively). This effect wasincreased further during next weeks, and at the end of treatment period(Week 5) the amount of sucrose solution drunk by these animals wascomparable to that of vehicle-treated controls and significantly higherthan that of vehicle-treated stressed animals (0.02 mg/kg: p<0.001, 0.2mg/kg: p-0.002).

At the lowest dose of 0.002mg/kg., THE COMPOUND had no significanteffect on the sucrose intake throughout the whole treatment period. Inconsequence, after five weeks of treatment the sucrose consumption ofstressed animals treated with this dose did not differ from the intakesof the vehicle-treated stressed animals (p=0.860) and was significantlylower than the intakes of vehicle-treated controls (p<0.01). One weekafter withdrawal from the treatment, the sucrose intakes were notsignificantly changed in all of THE COMPOUND -treated control (0.002mg/kg:p=0.2, 0.02 mg/kg: p=0.9, 0.2 mg/kg: p=0.4) and stressed animals(0.002 mg/kg: p=0.6, 0.02 mg/kg: p=0.8, 0.2 mg/kg: p=0.6).

Of course, clinical trials on humans may also be used to show theusefulness of the compound of the present invention in treatingdepression such as using the Abbreviated Hamilton Psychiatric RatingScale for Depression. This comprises a series of 17 categories in whichthe individual is rated, e.g., for depressed mood, guilt, suicidetendancies, insomnia, anxiety, etc., to reach a score which indicates tothe clinician whether or not the patient is suffering depression.

What is claimed is:
 1. A method of treating a patient for BipolarDisorder comprising administering to the patient an effective amount of(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolor its pharmaceutically acceptable acid addition salt.